ES2365633T3 - HYDRAZIDS OF AMIGDAL ACID. - Google Patents

Abstract

Compounds of the formula I ** Formula ** R3, R4, R5, R6, R7, R8, R9, R10, R11 are, respectively, independently of each other H, A, OSO2A, HaI, NO2, OR12, N (R12) 2, CN, O-COA, - [C (R12) 2] nCOOR12, O- [C (R12) 2] oCOOR12, SO3H, - [C (R12) 2] nAr, -CO-Ar, O- [C (R12) 2] nAr, -C (R12) 2] nHet, - [C (R12) 2] nC ≡ CH, O- [C (R12) 2] nC ≡ CH, - [C (R12) 2] nCON (R12) 2, - [C (R12) 2] nCONR12N (R12) 2, O- [C (R12) 2] nCON (R12) 2, O- [C (R12) 2] or CONR12N (R12) 2, NR12COA , NR12CON (R12) 2, NR12SO2A, N (SO2A) 2, COR12, S (O) mAr, SO2NR12 or S (O) mA, R3 and R4 together are also CH = CH-CH = CH, R3 and R4, R7 and R8 or R8 and R9 are also alkylene together with 3, 4 or 5 atoms of C, where one or two CH2 groups can be replaced by oxygen, A is unbranched or branched chain alkyl, with 1-6 atoms of C, wherein 1-7 atoms of H may be replaced by F, or cyclic alkyl with 3 to 7 atoms of C, Ar is phenyl, naphthyl or unsubstituted or mono, bi or trisubstituted by Hal, A, OR12, N (R12) 2, NO2, CN, phenyl, CON (R12) 2, NR12COA, N R12CON (R12) 2, NR12SO2A, COR12, SO2N (R12) 2, S (O) mA, - [C (R12) 2] n-COOR12 and / or - O [C (R12) 2] o-COOR12, Het it can be a saturated or unsaturated aromatic heterocycle with 1 to 4 atoms N, O and / or S, unsubstituted or mono, bi or trisubstituted by Hal, A, OR12, N (R12) 2, NO2, CN, COOR12, CON (R12 ) 2, NR12COA, NR12SO2A, COR12, SO2NR12, S (O) mA, = S, = NR12 and / or oxygen carbonyl (= O), R12 is H or A, Hal is F, Cl, Br or I, m is 0, 1 or 2, n is 0, 1, 2 or 3, or is 1, 2 or 3, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

Description

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The present invention is based on the task of finding new compounds with valuable characteristics, especially those that can be used to obtain medicaments.

The present invention comprises compounds and the use of compounds in which the inhibition, regulation and / or modulation of the kinase signal transduction, especially of human h-sgk kinase regulated by cell volume (human serum and) plays a role. glucocorticoid dependent kinase or SGK), likewise, pharmaceutical compositions containing these compounds, as well as the use of the compounds for the treatment of diseases associated with SGK.

SGK forms, together with the SGK-1, SGK-2 and SGK-3 isoforms a family of serine / threonine kinase proteins (WO 02/17893).

The compounds according to the invention are preferably selective inhibitors of SGK-1. They can also be inhibitors of SGK-2 and / or SGK-3.

The present invention comprises, in particular, compounds that inhibit, regulate and / or modulate the transduction of SGK signals, compositions containing said compounds, as well as methods for their use in the treatment of diseases associated with SGK and conditions such as diabetes (for example, diabetes mellius, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), adiposity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertonia, diseases of the cardiovascular system (for example, cardiac fibrosis after myocardial infarction, cardiac hypertrophy , heart failure and arteriosclerosis) and kidney diseases (such as glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and electrolyte elimination failures), in general, in all types of fibrosis and inflammatory processes (such as liver cirrhosis, pulmonary fibrosis, fibrous pancreatitis, rheumatism and osteoarthritis, Crohn's disease, bronchitis is chronic, radiogenic fibrosis, sclerodermatitis, cystic fibrosis, scar formation and Alzheimer's disease).

The compounds according to the invention can also inhibit the growth of tumor cells and tumor metastasis and are therefore suitable for tumor therapy.

The compounds according to the invention can also be used in the treatment of peptic ulcers, especially in forms generated by stress.

The compounds according to the invention are also used for the treatment of coagulopathies, such as dysfibrinogenemia, hypoproconvertinemia, hemophilia B, Stuart-Prower deficiency, lack of prothrombin complex, coagulopathy consumption, hyperfibrinolysis, immunocoagulopathy or complex coagulopathies, as well as in the case of neuronal irritability, for example, epilepsy. The compounds according to the invention can also be used in the treatment of glaucoma or cataracts.

The compounds according to the invention are also used in the treatment of bacterial infections as well as in an anti-infective therapy. The compounds according to the invention can also be used therapeutically for the increase of learning capacity and attention. In addition, the compounds according to the invention counteract cellular aging and stress and thereby increase life expectancy and maintain a good physical condition in old age.

The compounds according to the invention are also used in the treatment of tintinus.

Therefore, the identification of reduced compounds that specifically inhibit, regulate and / or modulate the transduction of SGK signals is desirable, which is also an object of the present invention.

It was found that the compounds according to the invention and their salts, in the case of good compatibility, possess very valuable pharmacological characteristics.

They have, especially, the inhibitory characteristics of SGK.

Therefore, the subject of the present invention are the compounds according to the invention as medicaments and / or medicinal active substances for the treatment and / or prophylaxis of the aforementioned conditions and the use of compounds according to the invention for obtaining a Pharmaceutical product for the treatment and / or prophylaxis of the aforementioned conditions and also a procedure for the treatment of the conditions

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mentioned comprising the administration of one or multiple compounds according to the invention, to a patient in need of said administration.

The host or patient may belong to any species of mammal, for example, to a species of primates, especially humans; rodents, including mice, rats and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental research, they also provide a model for the treatment of a human disease.

To identify a data transmission path and to check the interactions between different data transmission paths, different scientists developed models or systems of suitable models, for example, cell culture models (for example, Khwaja et al., EMBO, 1997 , 16, 2783-93) and models of transgenic animals (eg, White et al., Oncogene, 2001, 20, 7064-7072). To check certain levels of data transmission cascades, interacting compounds can be used to modulate the signal (for example, Stephens et al., Biochemical J., 2000, 351, 95-105). The compounds according to the invention can also be used as reagents for signaling pathway tests in animals and / or cell culture models or in the clinical diseases mentioned in the present declaration.

The measurement of kinase activity is a technique known to the specialist. Generic test systems for determining kinase activity with substrates, for example, histone (eg, Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or myelin basic protein, are described in the literature (for example, Campos-González, R. and Glenney, Jr., JR 1992, J. Biol. Chem. 267, page 14535).

For the identification of kinase inhibitors, different analysis systems are available. In the analysis of the proximity of the scintillation (Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) and the Flash Plate analysis the radioactive phosphorylation of a protein or peptide as a substrate with ATP is measured. If there is an inhibitory relationship, no radioactive signal or reduced resolution will be checked. Similarly, homogeneous time-resolved fluorescence resonance energy transfer technologies (HTR-FRET) and fluorescent polarization (FP) technology (Sills et al., J. of Biomolecular Screening, 2002, are useful as analysis procedures. 191214).

Other non-radioactive ELISA analysis procedures use specific phosphoantibodies (Phospho-AK). Phospho-AK only binds the phosphorylated substrate. This linkage can be checked with a second peroxidase-conjugated anti-aging antibody, through chemiluminescence (Ross et al., 2002, Biochem. J., 2002, 366, 977981).

CURRENT STATE OF THE TECHNIQUE

WO 00/62781 describes the use of drugs containing H-SGK human kinase inhibitor substances regulated by cell volume.

WO 2005037773 describes azinylaminoazoles as SGK inhibitors. WO 2006 105850 describes acylhydraziols as SGK inhibitors.

Other acylamigadic acid hydrazides are described as fungicides in WO96 / 17840 and in P. Lebrel, Tetrahedron 1988, 44, 4805-4814. Benzohydrazides of benzylides with an antibacterial effect are described in WO 02/070464 A2. The use of acylhydrazides for the treatment of bacterial infections is published in WO01 / 70213. Other acylhydrazone derivatives, among others, for the treatment of diabetes complications, are published in JP 11-106371.

The aromatic derivatives of the methoxy substitution acylhydrazone, for the treatment of cancer are described by T. Kametani et al. in Yakugaku Zasshi (1963), 83, 851-855 and in Yakugaku Zasshi (1963), 83, 844-847.

Other aromatic derivatives of acylhydrazone as sedative enhancers and to reduce blood pressure are described in JP 41-20699.

The use of kinase inhibitors in anti-infective therapy is described by C. Doerig in Cell. Mol. Biol. Lett.vol. 8, no 2A, 2003, 524-525.

The use of kinase inhibitors in adiposity is described by N. Perrotti in J. Biol. Chem. 2001, March, 23; 276 (12): 9406-9412.

The following bibliographical references describe the use of SGK inhibitors in the treatment of diseases:

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1: Chung EJ, Sung YK, Farooq M, Kim Y, Im S, Tak WY, Hwang YJ, Kim YI, Han HS, Kim JC, Kim MK. Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray. Mol Cells 2002; 14: 382-7.

2: Brickley DR, Mikosz CA, Hagan CR, Conzen SD. Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1). J Biol Chem. 2002; 277: 43064-70.

3: Fillon S, Klingel K, Wamtges S, Sauter M, Gabrysch S, Pestel S, Tanneur V, Waldegger S, Zipfel A, Viebahn R, Haussinger D, Broer S, Kandolf R, Lang F. Expression of the serine / threonine kinase hSGK1 in chronic viral hepatitis. Cell Physiol Biochem. 2002; 12: 47-54.

4: Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001; 21: 952-65

5: Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine / threonine survival kinase gene, sgk-1. J Biol Chem. 2001; 276: 16649-54.

6: Zuo Z, Urban G, Scammell JG, Dean NM, McLean TK, Aragon 1, Honkanen RE. Ser / Thr protein phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest. Biochemistry 1999; 38: 8849-57.

7: Buse P, Tran SH, Luther E, Phu PT, Aponte GW, Firestone GL. Cell cycle and hormonal control of nuclear cytoplasmic localization of the serum-and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells. A novel convergence point of anti-proliferative and proliferative cell signalling pathways. J Biol Chem. 1999; 274: 43064

70. 7253-63.

8: M. Hertweck, C. Gobel, R. Baumeister: C. leggans SGK-1 is the critical component in the Akt / PKB Kinase complex to control stress response and life span. Developmental Cell, Vol. 6, 577-588, April, 2004.

SUMMARY OF THE INVENTION

The present invention comprises compounds of the formula I

image 1

where R1, R2 are, independently of each other, H, CHO or acetyl, R3, R4, R5, R6, R7, R8, R9, R10, R11 are, respectively, independently of each other H, A, OSO2A, HaI, NO2, OR12, N (R12) 2, CN,

O-COA, - [C (R12) 2] nCOOR12, O- [C (R12) 2] oCOOR12, SO3H, - [C (R12) 2] nAr, -CO-Ar, O- [C (R12) 2 ] nAr, - [C (R12) 2] nHet, [C (R12) 2] nC = CH, O- [C (R12) 2] nC≡CH, - [C (R12) 2] nCON (R12) 2 , - [C (R12) 2] nCONR12N (R12) 2, O- [C (R12) 2] nCON (R12) 2, O [C (R12) 2] oCONR12N (R12) 2, NR12COA, NR12CON (R12) 2, NR12SO2A, N (SO2A) 2, COR12, S (O) mAr, SO2NR12 or S (O) mA,

R3 and R4 together are also CH = CH-CH = CH, R3 and R4, R7 and R8 or R8 and R9 are also together alkylene with 3, 4 or 5 C atoms, where one or two CH2 groups may be replaced by oxygen, A is unbranched or branched chain alkyl, with 1-6 C atoms, where 1-7 atoms of H can be replaced by F,

or cyclic alkyl with 3 to 7 C atoms,

Ar is phenyl, naphthyl or unsubstituted or mono, bi or trisubstituted by Hal, A, OR12, N (R12) 2, NO2, CN, phenyl, CON (R12) 2, NR12COA, NR12CON (R12) 2, NR12SO2A, COR12 , SO2N (R12) 2, S (O) mA, - [C (R12) 2] n-COOR12 and / or O [C (R12) 2] o-COOR12,

5 Het can be a saturated or unsaturated aromatic heterocycle with 1 to 4 N, O and / or S atoms, unsubstituted or mono, bi or trisubstituted by Hal, A, OR12, N (R12) 2, NO2, CN, COOR12, CON (R12) 2, NR12COA, NR12SO2A, COR12, SO2NR12, S (O) mA, = S, = NR12 and / or carbonyl oxygen (= O),

R12 is Ho A,

Hal is F, Cl, Br or I, 10 m is 0.1 or 2, n is 0, 1.2 or 3,

or is 1, 2 or 3 as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

The subject of the present invention is the compounds of the formula 1 and their salts, as well as a process for obtaining the compounds of the formula 1 according to claims 1-16, as well as their solvates, salts and stereoisomers for pharmaceutical use , characterized because

a) a compound of the formula II is reacted

image2

wherein R1, R7, R8, R9 R10 and R11 have the meaning indicated in claim 1, with a compound of the formula III

image 1

Wherein L is Cl, Br, I or a freely reactive or functionally modified OH group, R2, R3, R4, R5 and R6 have the meaning indicated in claim 1 and or b) a compound of the formula IV is reacted

image3

wherein R2, R3, R4, R5 and R6 have the meaning indicated in claim 1, with a compound of the formula V

image 1

10 where

L is Cl, Br, I or a free or functionally reactive modified OH group,

R1, R7, R8, R9 R10 and R11 have the meaning indicated in claim 1,

or

c) in a compound of the formula I a radical R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and / or R11 is converted into another radical R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and / or R11,

dissociating an ether through hydrolysis or hydrogenolysis and / or converting a base or acid of the formula I into one of its salts.

The object of the present invention are also the stereoisomers (E, Z isomers), as well as the hydrates and solvates of these compounds. Solvates of the compounds are understood as accumulations of inert solvent molecules in the compounds that are formed due to their force of mutual attraction. Solvates are, for example, mono or dihydrates or alcoholates.

Derivatives of pharmaceutical use are understood as, for example, the salts of the compounds according to the invention.

The term "effective amount" means the amount of the drug or a pharmaceutical active substance that causes a medicinal response in a tissue, system, animal or human being, which, for example, is sought or desired by a researcher or physician.

On the other hand, the expression "amount of therapeutic action" is an amount that, in comparison to the corresponding subject, which does not have this amount, has the following consequences: healing treatment

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improved, healing, prevention or elimination of a disease, a picture of a disease, a state of a disease, a medical condition, a nuisance or side effects or also the reduction of the progression of a disease, ailment or discomfort.

The term "amount of therapeutic action" also includes the amounts effective to raise normal physiological function.

The object of the invention are also mixtures of the compounds according to the invention, of the formula I, for example, mixtures of two diastereomers, for example, in a ratio of 1: 1, 1: 2, 1: 3, 1 : 4, 1: 5, 1:10, 1: 100 or 1: 1000.

Especially preferred are mixtures of stereoisomeric compounds, especially, the compounds according to the invention are present in the form of racemate.

For all radicals that occur multiple times, it is worth that their meanings are independent of each other.

In all cases, if the opposite is not expressly stated, the radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 have the meanings indicated in formula I.

A is alkyl, is unbranched (linear) or branched chain and has 1, 2, 3, 4, 5 or 6 atoms C. A is preferably methyl, in addition, ethyl, propyl, isopropyl, butyl, isobutyl, sec .-Butyl or tert-butyl, also, also pentyl, 1-, 2-or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2 -, 3-or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl -1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, preferably, for example, trifluoromethyl.

A is, especially preferably, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl , hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1trifluoroethyl.

Ac is acetyl, Bn is benzyl, Ms is -SO2CH3.

R1 is preferably H, CHO or acetyl, especially H.

R2 is preferably H,

R3, R4, R5, R6, R7, R8, R9, R10, R11 are, respectively, independently of each other, H, A, Hal, OR12 or O [C (R12) 2] nAr.

R3 is, especially preferably, H, A or Hal,

R6 is, especially preferably, OH,

R8 is, especially preferably, OH, A, phenoxy or Hal.

R4, R5, R7, R9, R10, R11 mean, especially preferably H or A.

R7, R10, R11 are, especially preferably, independently of each other, H or Hal.

R12 is, especially preferably, H.

Ar is, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m-

or p-tert.-butylphenyl, o-, mo p-hydroxyphenyl, o-, mo p-nitrophenyl, o-, mo p-aminophenyl, o-, mo p- (n-methylamino) phenyl, o-, mo p - (n-methylaminocarbonyl) -phenyl, o-, mo p-acetamidophenyl, o-, mo p-methoxyphenyl, o-, mo petoxyphenyl, o-, mo p-ethoxycarbonylphenyl, o-, mo p- (N, N- dimethylamino) -phenyl, o-, mo p- (n, n-dimethylaminocarbonyl) phenyl, o-, mo p- (N-ethylamino) -phenyl, o-, or p- (n, n-diethylamino) -phenyl, o-, mo p-fluorophenyl, o-, mo p-bromophenyl, o-, mo p-chlorophenyl, o-, mo p- (methyl sulfonamido) -phenyl, o-, mo p- (methylsulfonyl) -phenyl, o-, mo p-cyanphenyl, o-, mo p-ureidophenyl, o-, mo p-formylphenyl, o-, mo p-acetylphenyl, o-, mo p-aminosulfonylphenyl, o-, mo pcarboxyphenyl, o-, mo p-carboxymethyl-phenyl, o-, or p-carboxymethoxy-phenyl, preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorphenyl, 2 , 3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dibromophenyl, 2,4

or 2,5-dinitrophenyl, 2,5-or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4- Chlorine, 2-amino-5-chloro-or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl, 2,3diaminophenyl, 2, 3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5- dichlorophenyl, p

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iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluorine-3-chlorophenyl, 2-fluorine-4-bromphenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6methoxyphenyl, 3-chloro-6- methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluorine-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar is preferably, for example, unsubstituted or mono, bi or trisubstituted phenyl by Hal, A, OR2, SO2A, COOR2 or CN, particularly preferably, unsubstituted or mono phenyl, bi or trisubstituted by Hal and / or A, especially , Ar is phenyl.

Het means, independently of other substitutions, for example, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1, 2, 4-or 5-imidazolyl, 1-, 3 -, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazotyl, 3-, 4-or 5isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, preferably 1,2,3-triazol-1-, -4-o-5-yl, 1,2,4-triazol- 1-, 3-or 5-yl, 1-or 5-tetrazolyl, 1,2,3-oxadiazol-4-or -5-yl, 1,2,4-oxadiazol-3-or -5-yl, 1 , 3,4-thiadiazol-2-o -5-yl, 1,2,4thiadiazol-3-o -5-yl, 1,2,3-thiadiazol-4-or -5-yl, 3- or 4- pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 4-or 5isoindolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl , 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5 -, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-quinolinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 82h-benzo- [1,4] oxazinyl, preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4-or -5yl or 2, 1,3-benzoxadiazol-5-yl.

The heterocycle radicals can also be partially or totally hydrogenated.

Then Het can also be, for example, 2,3-dihydro-2-, -3-, -4-or -5-furyl, 2,5-dihydro-2-, -3-, -4-or 5- furyl, tetrahydro-2-o -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, - 4-o-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4-o -5-pyrrolyl, 1-, 2-or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4o -5-pyrazolyl, tetrahydro-1-, -3-or -4-pyrazolyl, 1,4-dihydro- 1-, -2-, -3-o -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5o -6-pyridyl, 1- , 2-, 3-or 4-piperidinyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-o -4-pyranyl, 1,4-dioxanyl, 1,3-dioxane2-, -4 -o-5-yl, hexahydro-1-, -3-o -4-pyridazinyl, hexahydro-1-, -2-, -4-o-5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1 , 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or -8-quinolyl, 1,2,3,4-tetrahydro-1 -, - 2 -, - 3-, -4-, -5-, -6-, -7-or -8-isoquinolyl, -2-, 3-, 5-, 6-, 7-or 8-3 , 4-dihydro-2h-benzo [1,4] oxazinyl, preferably 2,3-methylenedioxyphenyl, 3,4-methylendioxyphene lo, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5-or 6-yl, 2,3- (2-oxo-methylenedioxy) -phenyl or also , 4-dihydro-2H -1,5-benzodioxepin-6-or -7yl, preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxo-furanyl.

Het is preferably a saturated, unsaturated or aromatic mononuclear heterocycle with 1 to 2 N and / or O atoms, which can be unsubstituted or mono, bi or trisubstituted by A, Hal, OH and / or OA,

Het is, especially preferably, a mononuclear saturated heterocycle with 1 to 2 atoms of N and / or O, which may be unsubstituted or mono or bis-substituted by A,

In another embodiment, Het is, especially preferably, piperidinyl, pyrrolidinyl, morpholinyl or piperazinyl.

In another embodiment, Het is, especially preferably, furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or unsubstituted or mono or bi or trisubstituted piperazinyl by A, Hal , OH and / or OA.

The compounds of the formula I can have one or multiple chiral centers and are therefore presented in different stereoisomeric forms. Formula I comprises all these forms.

Correspondingly, the object of the invention especially comprises those compounds of the formula I in which at least one of the radicals mentioned has one of the indicated preferred meanings. Some preferred sets of compounds can be expressed by the following partial formulas Ia to Ig, which correspond to formula I and in which unspecified radicals have the meaning of formula I, where, however, they mean the following:

In Ia, R1 is Ho CHO,

R2 is H,

in Ib, R3, R4, R5, R6, R7, R8, R9 R10, R11 are, respectively, independently of each other,

H, A, Hal, OR12 or O- [C (R12) 2] nAr;

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in Ic, R6 is OH; in Id, R3 is H, A or Hal, in Ie R8 is OH, A, phenoxy or Hal, in If R4, R5, R7, R9, R10, R11 is H or A, in Ig R7, R10, R11 are, respectively independently of each other, H or Hal, in Ih Ar is unsubstituted or mono, bi or trisubstituted phenyl by Hal and / or A in Ii Ar is phenyl; in Ij Het it is a saturated, unsaturated or aromatic mononuclear heterocycle with 1 to 2 N and / or O atoms which can be unsubstituted or mono, bi or trisubstituted by A, Hal, OH and / or OA in Ik, Het is a mononuclear saturated heterocycle with 1 to 2 atoms of N and / or O, which can be unsubstituted or mono

or replaced by A,

in Il Het it is furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, unsubstituted or mono or bi or trisubstituted morpholinyl or piperazinyl by A, Hal, OH and / or OA. in Im, R1 is H or CHO, R2 is H, R3, R4, R5, R6, R7, R8, R9, R10, R11 are, respectively, independently of each other, H, A, Hal, OR12 or O

[C (R12) 2] nAr, in In, R1 is H or CHO, R2 is H, R3 is H, A or Hal, R4, R5, R7, R9, R10, R11 are H or A, R6 is OH, R8 is OH, A, phenoxy or Hal, in Io R1 is H, CHO or acetyl, R2 is H, R3 is H, A or Hal, R4, R5, R7, R10, R11 are, respectively independently of each other, H, A or Hal, R6 is OH, R8 is OH, A, phenoxy or Hal, R9 is H, Hal or OA, R8 and R9 together are also methylenedioxy, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all

proportions

Especially preferably, the compounds of the formula I are selected from the set

Do not

structural formula

"A15"

N ’- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-chloro-4,6-dihydroxy-benzohydrazide

"A16"

N ’- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-methyl-4,6-dihydroxy-benzohydrazide

"A17"

N ’- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-ethyl-4,6-dihydroxy-benzohydrazide

Compounds according to the invention and also the raw materials for obtaining them are otherwise obtained through known methods, such as those described in the literature (for example, in fundamental works such as

5 Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg-Thieme Publishing House, Stuttgart), namely, under known reaction conditions and suitable for such conversions. In turn, known variants not mentioned in greater detail here can also be used.

The raw materials can also be formed in situ, so that they are not isolated from the reaction mixture, but are converted immediately until the compounds according to the invention are obtained.

10 The initial compounds in general are known. If they are new, they can also be obtained by known methods.

The compounds of the formula I can preferably be obtained by converting a hydrazide of the formula II with a compound of the formula III.

The conversion is carried out with methods known to the specialist. The conversion is done, in general, in a

Inert solvent, if any, in the presence of an acidic bonding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline, or of a surplus of the carboxy component of the formula III.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzole, toluene.

or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloro, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert.-butanol; ethers like

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diethyl ether, diisopropylether, tetrahydrofuran (THF) or dioxane; glycol ether such as ethylene glycol monomethyl ether or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglymes); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DM-SO); carbon-sulfur; carboxylic acids such as formic acid or acetic acid; nitrogen compounds such as nitromethane

or nitrobenzole; esters such as ethyl acetate or mixtures of the solvents mentioned.

Water or DMF is especially preferred as solvent.

The addition of a hydroxide or an alkali or alkaline earth carbonate or bicarbonate, or another salt in a weak acid of alkali or alkaline earth metals, preferably, of potassium, sodium, calcium or cesium may also be suitable.

The reaction time is, depending on the conditions applied, between a few minutes and 14 days, the reaction temperature, between approximately -30 ° and 140 °, usually between -10 ° and 90 °, especially preferably , between 0 ° and 70 °.

In the compounds of the formula III, L is preferably Cl, Br, I or a free or derivative OH group capable of reacting, for example, an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C atoms, ( preferably, methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably, phenyl- or ptolylsulfonyloxy).

Such radicals for the activation of the carboxy group in typical acylization reactions are known in the literature (for example, in standard works such as Houben-Weyl, Methoden der Organischen Chemie, (Organic Chemistry Methods), Editorial Georg-Thieme, Stuttgart ).

Activated esters are suitably formed in situ, for example, by adding HOBt or N-hydroxysuccinimide.

The compounds of the formula I can also be obtained, preferably, by converting a hydrazide of the formula IV with a compound of the formula V.

The conversion is generally carried out in an inert solvent, in the presence of an acid binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline, or of a surplus of the carboxy component of the formula V.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzole, toluene.

or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloro, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert.-butanol; ethers such as diethyl ether, diisopropylether, tetrahydrofuran (THF) or dioxane; glycol ether such as ethylene glycol monomethyl ether or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglymes); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DM-SO); carbon-sulfur; carboxylic acids such as formic acid or acetic acid; nitrogen compounds such as nitromethane

or nitrobenzole; esters such as ethyl acetate or mixtures of the solvents mentioned.

The addition of a hydroxide or an alkali or alkaline earth carbonate or bicarbonate, or another salt in a weak acid of alkali or alkaline earth metals, preferably, of potassium, sodium, calcium or cesium may also be suitable.

The reaction time is, depending on the conditions applied, between a few minutes and 14 days, the reaction temperature, between approximately -30 ° and 140 °, usually between -10 ° and 90 °, especially preferably , between 0 ° and 70 °.

In the compounds of the formula V, L is preferably Cl, Br, I or a free or derivative OH group capable of reacting, for example, an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C atoms, ( preferably, methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably, phenyl- or ptolylsulfonyloxy).

Such radicals for the activation of the carboxy group in typical acylization reactions are known in the literature (for example, in standard works such as Houben-Weyl, Methoden der Organischen Chemie, (Organic Chemistry Methods), Editorial Georg-Thieme, Stuttgart ).

Activated esters are suitably formed in situ, for example, by adding HOBt or N-hydroxysuccinimide.

The compounds of the formula I can also be obtained by converting a radical R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and / or R11 into another radical R1, R2, R3, R4, R5 , R6, R7, R8, R9, R10 and / or R11, dissociating an ether through hydrolysis or hydrogenolysis.

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The dissociation of an ether is carried out with methods known to the specialist.

A standard method for the dissociation of ether, for example, from a methyl ether, is the use of boron tribromide.

Hydrogenolytic separation groups, for example, the dissociation of a benzyl ether, can be dissociated, for example, by treatment with hydrogen, in the presence of a catalyst (for example, a noble metal catalyst, such as palladium, conveniently , on a carrier like coal). Suitable solvents are those mentioned, especially, for example, alcohols such as methanol or ethanol or amides, such as DMF. Hydrogenolysis is generally carried out at temperatures between approximately 0 and 100 ° and at pressures between approximately 1 and 200 bar, preferably at 20-30 ° and 1-10 bar.

The esters can be saponified, for example, with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.

Pharmaceutical salts and other forms

The compounds according to the invention mentioned can be used in their definitive non-saline form. On the other hand, the present invention also comprises the use of these compounds in the form of their pharmacologically safe salts, which can be derived from different acids and bases, organic or inorganic, according to known ways of proceeding. Pharmaceutically harmless salt forms of the compounds of the formula I are obtained, in large part, in a conventional manner. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by converting the compound with a suitable base to obtain a base addition salt. Such bases are, for example, alkali metal oxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide, alkaline earth metal hydroxide such as barium hydroxide and calcium hydroxide; alkaline earth metal alcoholates, for example, potassium ethanolate and sodium propanolate; as well as different organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of the formula I are also among them. In the case of certain compounds of the formula I, acid addition salts may be formed by treating these compounds with pharmaceutically harmless organic or inorganic acids, for example halogenated hydrogens, such as hydrogen bromide, hydrogen chloride, hydrogen iodide , other mineral acids and their corresponding salts, such as sulfate, nitrate or phosphate and the like, as well as alkylsulfonates and monoarylsulfonates, such as ethane sulphonate, toluenesulfonate and benzol sulphonate, as well as other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Correspondingly, among the pharmaceutically harmless acid addition salts of the compounds of the formula I are the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzolsulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorated, camphor sulfulfonate, caprylate, chloride, chlorbenzoate, citrate, cyclopentanpropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, hemisphere , hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaposphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalate, nitrate , pectinate, persulfate, penylacetate, 3-phenylpropionate, phosphate, phosphone to, phthalate, without the list being exclusive.

In addition, among the basic salts of the compounds according to the invention are the aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III) salts. , manganese (II), potassium, sodium and zinc, without the list being exclusive. Among the salts mentioned above, ammonium is preferred; alkali metal sodium and potassium salts, as well as alkaline earth metal salts such as calcium and magnesium. Among the salts of the compounds of the formula I, derived from non-toxic, pharmacologically safe organic bases, are the salts of primary, secondary and tertiary amines, among them, also natural substituted amines, cyclic amines as well as ion exchange resins, for example, arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorphamine, N-ethyl , glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethanolamine, triethylamine, trimethyl amine - (hydroxymethyl) -methylamine (tromethamine), which does not mean that the list is exclusive.

The compounds of the present invention, which contain basic groups containing nitrogen, can be quaternized with the agents such as alkylhalogenides (C1-C4), for example, methyl, ethyl, isopropyl and tert. butylchloride, bromide and iodide; di (C1-C4) alkyl sulfates, for example, dimethyl, diethyl and diamyl sulfates, alkylhalogenides (C10-C18), for example, decyl, dodecyl, lauryl, myristyl and stearylchloride, bromide and iodide; as well as aryl- (C1-C4) alkylhalogenides, for example, benzylchloride and phenethyl bromide. Compounds according to the invention can be obtained with such salts, which can be mixed with both water and oil.

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Among the preferred pharmaceutical salts mentioned are acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate , sulfosalicylate, tartrate, thiomalate, tosolate and tromethamine, which should not mean that the list is exclusive.

The acid addition salts of the basic compounds of the formula I are obtained by contacting the free base form with a sufficient amount of the desired acid, obtaining the salt in the usual manner. The free base can be regenerated in the usual way thanks to the contact of the salt form with a base and the isolation of the free base. Free base forms differ, in a certain sense, from their corresponding saline forms in regard to certain physical qualities, such as solubility in polar solvents; however, within the framework of the invention, the salts correspond to their respective free base forms.

As we have already mentioned, pharmaceutically harmless base addition salts of the compounds of the formula I are obtained with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N’dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base addition salts of the acidic compounds, according to the invention, of the formula I, are obtained by contacting the free acid form with a sufficient amount of the desired base, obtaining the salt in the usual way. The free acid can be regenerated in the usual way thanks to the contact of the saline form with an acid and the isolation of the free acid. The forms of free acids differ, in a certain sense, from their corresponding saline forms, with regard to certain physical qualities, such as solubility in polar solvents; however, within the scope of the invention, the salts correspond to their respective free acid forms.

If a compound according to the invention contains more than one group that can form those pharmaceutically harmless salts, the invention also comprises multiple salts. Among the typical multiple salt forms are, for example, bitartrate, diacetate, dipumate, dimeglumine, diphosphate, disodium and trihydrochloride, said list is not restrictive.

Taking into account the above, we can see that in this context "pharmaceutically harmless salt" means an active substance that contains a compound of the formula I in the form of one of its salts, especially when this salt form gives improved pharmacological characteristics to the active substance, compared to the free form of the substance or other saline form of the substance that was previously used. The pharmacologically safe saline form of the active substance can also give this active substance a first desired pharmacokinetic characteristic, which it did not previously present, and may even positively influence the pharmacodynamics of this active substance in relation to its therapeutic action in the body.

Due to their molecular structure, the compounds according to the invention of the formula I can be chiral and, therefore, can be presented in different enantiomeric forms. They can be found in racemic form or in optically active form.

Since the pharmaceutical effectiveness of the racemates or stereoisomers of the compounds according to the invention can be differentiated, it may be desirable to use the enantiomers. In these cases, the final product or even the intermediate products, in enantiomeric compounds, can be separated by chemical or physical measures known by the specialist, or used as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixture, through conversion with an optical action separator. Suitable separators are, for example, optical-acting acids, such as R and S forms of dextrotartaric acid, diacetyldextrotartaric acid, dibenzoyldextrotartaric acid, tonsillar acid, malic acid, lactic acid, suitable N-protecting amino acids (for example, N-benzoylproline or Nbenzolsulfonylproline) or the different camphor sulfonic acids, of optical action. Also advantageous is an enantiomeric chromatographic separation by an optical action separator (for example, dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivative methacrylate polymers fixed on silica gel). Suitable eluents are, for this purpose, aqueous or alcoholic mixtures of solvents, for example, hexane / isopropanol / acetonitrile, for example, in a ratio of 82: 15: 3.

The object of the present invention is, in addition, the use of the compounds and / or their physiologically safe salts for obtaining medicaments (pharmaceutical preparations), especially, in non-chemical processes. Furthermore, they can be suitably dosed together with at least one solid, liquid and / or semi-liquid excipient or adjuvant and, possibly, in combination with one or multiple active substances.

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Also subject to the invention are medicaments that contain at least one compound according to the invention and / or its solvates and stereoisomers for pharmaceutical use, including mixtures thereof in all proportions, as well as, if appropriate, excipients and / or adjuvants

Pharmaceutical formulations can be supplied in the form of dosage units containing a predetermined amount of active substance per dosage unit. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably, 5 mg to 100 mg of a compound according to the invention, according to the state of the disease to be treated, the route of delivery and the age, weight and condition of the patient, or pharmaceutical formulations can be supplied in the form of predetermined dosage units containing a certain amount of active substance per dosage unit. Preferred dosage unit formulations are those that contain a daily dose or a partial dose, as indicated above, or a corresponding fraction, of an active substance. Furthermore, said pharmaceutical formulations can be obtained with a procedure known in the pharmaceutical sector.

Pharmaceutical formulations can be adapted to the desired appropriate delivery route, for example, to the oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular) routes , intravenous or intradermal). Said formulations can be obtained with all the procedures known in the pharmaceutical sector, for example, by mixing the active substance with the carrier (s) or auxiliary substances.

Formulations adapted for oral delivery can be supplied in separate units, for example, in capsules or tablets; powder or granulate; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foaming foods; or in liquid emulsions of oil in water or water in oil.

For example, in the case of oral administration in the form of a tablet or capsule, the active component can be combined with an inert, oral, non-toxic and pharmacologically safe carrier, for example, ethanol, glycerin, water or the like. The powder is obtained by mixing the compound, crushing to a suitable fine size, with a pharmaceutical carrier, similarly crushed, for example, an edible carbohydrate, such as starch or handyman. A flavoring, preservatives, dispersing agents and colorants can also be added.

The capsules are manufactured by obtaining a powder mixture as described above and filling molded gelatin capsules with it. To the powder mixture, lubricants and glidants, for example, highly dispersed silicic acid, talcum, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added before the filling process. An effervescent or solubilizing agent, for example, agar-agar, calcium or potassium carbonate, can also be added to improve the availability of the drug after ingestion.

In addition, if desired or when necessary, binder, lubricant and effervescent substances as well as suitable colorants can be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, for example, glucose or beta-lactose, corn sweeteners, natural and synthetic gum, for example, acacia, traganto or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, among Others Among the lubricants used in these dosage forms are sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, among others. Among the effervescent agents are, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, among others. The tablets are formulated, for example, by making a powder mixture, granulating

or drying by pressing, adding a lubricant and an effervescent agent and pressing everything until tablets are obtained. A powder mixture is obtained by mixing a suitably reduced compound with a solvent or a base, as described above and, eventually, with a binder, for example, carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution retarder. , for example, paraffin, a resorption accelerator, for example, a quaternary salt and / or an absorbent, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by moistening it with a binding substance, for example, a syrup, a starch paste, acacia mucilage or solutions of polymer or cellulose materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a pill machine, in which irregularly shaped pieces are formed that are broken to obtain granules. The granules can be greased by the addition of stearic acid, a stearic salt, talc or mineral oil, to avoid adhesion in the tablet molds. The greased mixture is then pressed into tablets. The compounds according to the invention can also be combined with an inert free current support substance, and then they are pressed directly into pellets, without passing through the granulation or dry pressing steps. It can have a transparent or non-transparent protective layer, consisting of a shellac seal, a layer of sugar or polymer material and a layer of wax shine. To these coatings dyes can be added to distinguish between different dosage units.

Oral liquids, for example, syrups and elixirs, can be obtained in the form of dosage units, so that a given amount has a predetermined amount of the compound. The syrups can be

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obtained by dissolving the compounds in an aqueous solution with a suitable flavor, while elixirs are obtained using a non-toxic alcoholic vehicle. The suspensions can be formulated through dispersion of the compound in a non-toxic vehicle. Solubilizers and emulsifiers can also be added, for example, ethoxylated stearyl alcohols and polyoxyethylene sorbitol ether, preservatives, flavoring additives, for example, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, or the like.

Dosage unit formulations for oral administration can also be incorporated, if necessary, into microcapsules. The formulation can also be obtained by prolonging or delaying the release, for example, by coating or incorporating the particular material in polymers, waxes, or the like.

The compounds according to the invention as well as their salts and solvates can also be supplied in the form of liposome delivery systems, for example, small unilamellar vehicles, large unilamellar vehicles and multilamellar vehicles. Liposomes can be formed by different phospholipids, for example, cholesterol, stearylamine or phosphatodylcholines.

The compounds according to the invention and their salts and solvates can also be supplied using monoclonal antibodies as individual carriers, to which the binding molecules are coupled. The compounds can also be coupled to soluble polymers as suitable medicament carriers. Such polymers may be polyvinylpyrrolidone, copolymer of Pirano, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylapartamide phenol or polyethylene oxide polylysine, substituted with palmitoyl radicals. In addition, the compounds may be coupled to a class of biodegradable polymers, suitable for achieving a controlled release of a medicament, for example, polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyortoester, polyacetals, cross-linked polyhydroxypyran, polycyanoacrylates and copolymers amphipathic hydrogels.

Pharmaceutical formulations adapted to transdermal administration can be supplied as an independent patch, with close contact with the epidermis of the recipient. Thus, for example, the active substance of the patch can be supplied by iontophoresis, as described in general lines in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds adapted to topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye, or other external tissue, for example, the mouth and the skin, the formulations are preferably applied as topical ointment or cream. In the case of the formulation of an ointment, the active substance can be applied with a paraffinic cream base or that can be mixed with water. Alternatively, the active substance can be formulated with an oil-in-water cream base or a water-in-oil base.

Among the pharmaceutical formulations suitable for topical application in the eye are eye drops, in which the active substance is dissolved or suspended in a suitable carrier, especially in an aqueous solvent.

Pharmaceutical formulations adapted to topical application include lozenges, lozenges and mouthwashes.

Pharmaceutical formulations adapted to rectal administration can be supplied in the form of suppositories or enemas.

Pharmaceutical formulations adapted to nasal administration, in which the carrier substance is a solid substance, contain a coarse powder with a particle size in the range of, for example, 20-500 micrometers, supplied in the same manner as the snuff , that is, by rapid inhalation through the nasal passages from a container with the powder, which is held near the nose. Formulations suitable for administration as a nasal spray or nose drops with a liquid as a support substance comprise solutions of the active substance in water or oil.

Pharmaceutical formulations suitable for administration by inhalation comprise fine particle powders or mists that can be obtained by different types of dosers under pressure, with aerosols, nebulizers or insufflators.

Pharmaceutical formulations adapted to vaginal administration can be applied in the form of pessaries, buffers, creams, gels, pastes, foams or spray formulations.

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Among the pharmaceutical formulations suitable for parenteral administration are sterile injectable aqueous or non-aqueous solutions, antioxidants, buffers, bacteriostats and solutes, through which the formulation is isotonicized with the blood of the recipient to be treated; as well as sterile aqueous and non-aqueous suspensions that may contain suspending and thickening agents. The formulations can be supplied in single-dose or multi-dose containers, for example, in sealed ampoules and bottles, and stored in the cold-dried (lyophilized) state, so that for injection it is only necessary to add the carrier liquid, by example, water, just before use. Solutions for injection and suspensions obtained according to the recipe can be obtained from powders, granules and sterile tablets.

It is understood that the formulations may contain, in addition to the aforementioned components, other usual means in the area of the specialty, as regards the respective type of formulation; for example, formulations suitable for oral administration may contain flavorings.

A therapeutically effective amount of a compound of the present invention depends on a number of factors, including, for example, the age and weight of the human or animal being, the precise state of the disease that the treatment requires, as well as its degree of complexity, the composition of the formulation, as well as the route of administration, and is determined, finally, by the doctor or veterinarian who performs the treatment. However, an effective amount of a compound according to the invention for treatment is, in general, in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammal) per day and, especially, in the range of 1 to 10 mg / kg body weight per day. That is, for an adult mammal weighing 70 kg, the actual amount per day would usually be between 70 and 700 mg, likewise, this amount can be administered in a single dose per day or, usually, in a series of partial doses (for example, two, three, four, five or six) per day, so that the total dose per day is the same. An effective amount of a salt or a solvate can be determined as part of the effective amount of the compound according to the invention itself. It can be assumed that similar dosages are suitable for the treatment of other disease states than those mentioned.

Also subject to the invention are medicaments containing at least one compound according to the invention and / or its salts and stereoisomers for pharmaceutical use, including mixtures thereof in all proportions, and at least one other substance of action. medicinal.

The object of the invention is also a set (kit) consisting of separate packages of (a) an effective amount of a compound according to the invention and / or its salts, solvates and stereoisomers for pharmaceutical use, including mixtures thereof in all the proportions, and (b) an effective amount of another medicinal action substance.

The set contains suitable containers, such as boxes, individual bottles, bags or ampoules. The set may contain, for example, separate ampoules in which there is an effective amount of a compound according to the invention and / or its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions, and an effective amount. of another medicinal active substance, dissolved or in lyophilized form.

UTILIZATION

The present compounds are suitable as pharmaceutical active substances for mammals, especially for humans, for the treatment of diseases associated with SGK.

It is the object of the present invention, therefore, to use compounds according to the invention, as well as their salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions, to obtain a medicament for the treatment of diseases. in which the inhibition, regulation and / or modulation of the kinase signal transduction play a role. In this case, the SGK is preferred.

The use of compounds according to claim I is preferred, as well as their salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions, for obtaining a medicament for the treatment of diseases in which the inhibition is influenced of the SGK, through the compounds according to claim I.

The present invention comprises the use of the compounds according to the invention, according to claim 1, and / or their physiologically harmless salts and solvates for obtaining a medicament for the treatment or prevention of diabetes (for example, diabetes mellius, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), adiposity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertonia, diseases of the cardiovascular system (e.g., cardiac fibrosis after myocardial infarction, cardiac hypertrophy, heart failure and arteriosclerosis) and diseases renal diseases (such as glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and electrolyte elimination failures), in general, in all types of fibrosis and inflammatory processes (such as liver cirrhosis, pulmonary fibrosis, fibrous pancreatitis, rheumatism and osteoarthritis, Crohn's disease, bronchitis chronic, radiogenic fibrosis, sclerode rmatitis, cystic fibrosis, scar formation and Alzheimer's disease).

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The compounds according to the invention can also inhibit the growth of cancer, tumor cells and tumor metastasis and are therefore suitable for tumor therapy.

The compounds according to the invention are also used for the treatment of coagulopathies, such as dysfibrinogenemia, hypoproconvertinemia, hemophilia B, Stuart-Prower deficiency, lack of prothrombin complex, coagulopathy consumption, hyperfibrinolysis, immunocoagulopathy or complex coagulopathies, as well as in the case of neuronal irritability, for example, epilepsy. The compounds according to the invention can also be used in the treatment of glaucoma or cataracts.

The compounds according to the invention are also used in the treatment of bacterial infections as well as in an anti-infective therapy. The compounds according to the invention can also be used therapeutically for the increase of learning capacity and attention.

The use of compounds according to claim 1 is preferred, as well as their salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions, for obtaining a medicament for the treatment or prevention of diabetes, adiposity, syndrome metabolic (dyslipidemia), systemic and pulmonary hypertonia, diseases of the cardiovascular system and kidney diseases, in general, in all types of fibrosis and inflammatory processes, cancer, tumor cells, tumor metastases, coagulopathies, neuronal irritability, glaucoma, cataracts, bacterial infections as well as in an anti-infective therapy, to increase learning capacity and attention, as well as for the treatment and prophylaxis of cell aging and stress.

In the case of diabetes, it is preferably diabetes mellius, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.

In the case of cardiovascular diseases, it is preferably cardiac fibrosis after myocardial infarction, cardiac hypertrophy, heart failure and arteriosclerosis.

In the case of kidney diseases, these are glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and failures in the elimination of electrolytes.

In the case of fibrosis and inflammatory processes, it is liver cirrhosis, pulmonary fibrosis, fibrous pancreatitis, rheumatism and atrosis, Crohn's disease, chronic bronchitis, radiogenic fibrosis, sclerodermatitis, cystic fibrosis, scar formation and Alzheimer's disease.

ANALYSIS

The compounds according to the invention, described in the examples, were evaluated in the analyzes described below, and were found to have a kinase inhibitory action. Other analyzes are known from the literature and could be performed simply by the specialist (see, for example, Dhanabal et al., Cancer Res. 59: 189-197; Xin et al., J. Biol. Chem. 274: 9116-9121; Sheu et al., Anticancer Res. 18: 4435-4441; Ausprunk et al., Dev. Biol. 38: 237-248; Gimbrone et al., J. Natl. Cancer Inst. 52: 413-427 ; Nicosia et al., In Vitro 18: 538-549).

The inhibition of the protein kinase SGK1 can be determined by means of a linkage testing procedure with filters.

Hereinafter, and above, all temperature indications are made in ° C. In the following examples, "usual processing" means: If necessary, water is added, if necessary, the pH values between 2 and 10 are regulated according to the constitution of the final product, extracted with ethyl acetate or dichloromethane, is separated, the organic phase is dried by sodium sulfate, evaporated and purified by chromatography on silica gel and / or through crystallization. Rf values on silica gel; eluent: ethyl acetate / methanol 9: 1.

Mass spectrometry (MS): EI (electronic shock ionization) M +

FAB (accelerated atom bombardment) (M + H) +

ESI (electrospray ionization) (M + H) + (if not indicated otherwise)

Example 1

The obtaining of N '- [2- (3,4-difluoro-phenyl) -2-hydroxy-acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide ("A1") is carried out analogously to following scheme:

image 1

N2H5OH monoacylates with 2,4-dibenzyloxy-6-methyl-benzic acid. Product obtained: 2,4-dibenzyloxy-6-methylbenzohydrazide (63%); F. 136-137˚.

image 1

5 2,4-Dibenzyloxy-6-methyl-benzohydrazide is hydrogenated. Product obtained: 2,4-dihydroxy-6-methyl-benzohydrazide (89%); F. 226˚ (decomposition).

1.3 282 mg of 3,4-difluoro-radicalic acid, 410 mg of 2,4-dihydroxy-6-methyl-benzohydrazide, 431 mg of 1-ethyl-3- (3dimethylaminopropyl) -carbodiimides (WSCD) and 164 mg of 1-hydroxybenzotriazoles (HOBt) stir 3 h in 1.5 ml of DMF. The procedure is customary and the silica gel chromatography is carried out. The unit fractions that

10 contain the product meet, reduce and crystallize from EtOAc / petroleum ether. Result: 250 mg of "A1" (46%), F. 220 C.

Similarly the following compounds are obtained:

fifteen

Do not

structural formula F. [˚C]

"A2"

N ’- [2-hydroxy-2- (3-phenoxy-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 177-178

"A3"

N ’- (2-hydroxy-2-phenyl-acetyl) -2,4-dihydroxy-6-methyl-benzohydrazide 188-189

"A4"

N ’- [2-hydroxy-2- (3-chloro-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 215

(continued) (continued) (continued) (continued) (continued)

Do not

structural formula F. [˚C]

"TO 5"

N ’- [2-hydroxy-2- (3-trifluoromethyl-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 226

"A6"

N ’- [2-acetoxy-2- (3-chloro-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 98-100

"A7"

N ’- [2-hydroxy-2- (3-fluorine-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 215-216

Do not

structural formula F. [˚C]

"A8"

N ’- [2-hydroxy-2- (3,5-difluoro-phenyl) -acetyl] 2,4-dihydroxy-6-methyl-benzohydrazide 215-217

"A9"

N ’- [2-hydroxy-2- (2,3,4,5,6-pentafluor-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 224-225

"A10"

N ’- (2-benzo [1,3] dioxol-5-yl-2-hydroxy-acetyl) -2,4-dihydroxy-6-methyl-benzohydrazide 215-216

Do not

structural formula F. [˚C]

"A11"

N ’- [2-hydroxy-2- (3-hydroxy-4-methoxy-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 126-128

"A12"

N ’- [2-hydroxy-2- (3-chloro-phenyl) -acetyl] -2,4-dihydroxy-5-chloro-benzohydrazide 221-222

"A13"

N ’- [2-hydroxy-2- (3-chloro-phenyl) -acetyl] -3-chloro-2-ethyl-4-hydroxy-benzohydrazide 164-165

Do not

structural formula F. [˚C]

"A14"

N ’- [(R) -2- (3-Chloro-phenyl) -2-hydroxy-acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 234-235

"A19"

N ’- [2-hydroxy-2- (3-methyl-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 222-223

"TO 20"

N ’- [2-hydroxy-2- (3,4-difluoro-phenyl) -acetyl] -2,4-dihydroxy-5-methyl-benzohydrazide 202-203

"A21"

N ’- [2-formyloxy-2- (3,4-difluoro-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide 92-93 (decomposition)

Do not

structural formula F. [˚C]

"A22"

N ’- [2-hydroxy-2- (3,4-difluoro-phenyl) -acetyl] -2,4-dihydroxy-6-ethyl-benzohydrazide 189-191

"A23"

N ’- [2-hydroxy-2- (3,4-difluoro-phenyl) -acetyl] -4-hydroxy-2-ethyl-3-methyl-benzohydrazide 191

Example 2

Obtaining of N ’- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-chloro-4,6-dihydroxy-benzohydrazide (" A15 ")

image 1

720 mg of N '- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-chloro-4,6-dihbenzyloxy-benzohydrazide in 20 ml of THF + 0.2 ml of 32% HCl they are hydrogenated in 360 mg of Pd / C with the calculated amount of H2. The hydrogenation solution is reduced and silica gel chromatography is performed. The unit fractions containing the product meet,

10 reduce and crystallize from EtOAc.

Result: 310 mg (65%) of "A15" F. 230-231 ˚.

Similarly the following compounds are obtained:

Do not

structural formula F. [˚C]

"A16"

N ’- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-methyl-4,6-dihydroxy-benzohydrazide 214-215

"A17"

N ’- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-ethyl-4,6-dihydroxy-benzohydrazide 233-234

Example 3

Obtaining of N ’- (2-hydroxy-2-phenyl-acetyl) -2-methyl-4,6-dihydroxy-benzohydrazide (" A18 ")

image 1

5 1.6 g of 2,4-dihydroxy-6-methyl-benzoic acid are refluxed with 4 ml of SOCl2 until a clear solution is obtained. The SOCl2 is extracted, then evaporated twice with CH2Cl2 until dry. The acid chloride is dissolved in 3 ml of DMF and 1.14 g of tonsillar acid hydrazide is added. After stirring 2 hours at room temperature, it is poured onto H2O, extracted with EtOAc, dried and reduced to a small volume. Result: 1.49 g (50%) of "A18" F. 188-189 ˚.

10 Alternative procurement (example 4):

1.82 g of 2,4-dihydroxy-6-methyl-benzohydrazide are dissolved in 10 ml of DMF. Slowly 1.71 g of tonsilic acid chloride is added. After stirring 2 hours at room temperature, it is poured onto H2O, extracted with EtOAc, dried and reduced to a small volume. Result: 2.16 g (68%) of "A18" F. 188-189 ˚.

Synthesis of precursors 15 Example 5

N '- [2-hydroxy-2- (3-hydroxyphenyl) -acetyl] -2,4-dibenzyloxy-6-methyl-benzohydrazide The substance is obtained from 2,4-dibenzyloxy-6-methyl-benzohydrazide and 3-hydroxyamigdálic acid with a 47% yield, analogous to example 1, F. 181-182˚ (from Me2COH / Et2O).

image 1

In a similar way the compounds are obtained:

N '- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-chloro-4,6-dibenzyloxy-benzo-hydrazide, F. 160-162˚ (from Me2COH / Et2O), 61% yield and N '- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2,4-dibenzyloxy-6-ethyl-benzohydrazide, F. 205-206˚ (of Me2COH / Et2O), 90 % yield

Example 6

2,4-bis-benzyloxy-6-ethyl-benzaldehyde

image4

1.9 g of dihydroxy-6-ethyl-benzaldehyde, 3.48 ml of benzyl chloride and 4.7 g of K2CO3 are mixed in 5.2 ml of DMF for 2 h at 90˚. The result is diluted with EtOAc and washed with water. The organic phase is dried with Na2SO4, reduced and subjected to silica gel chromatography. The unit fractions containing the product are collected and reduced. The remaining oily product solidifies after a few days of rest. It is treated with ether / petroleum ether 1: 1 and

15 3.5 g (88%) of 2,4-bis-benzyloxy-6-ethylbenzaldehyde are obtained, which is colored in contact with air.

3-Chloro-2-ethyl-4-hydroxy-benzoic acid is benzylated in an analogous way: 3-Chloro-2-ethyl-4-benzyloxy-benzoic acid is obtained in a yield of 78%, F. 208-210˚.

Example 7

2,4-bis-benzyloxy-6-ethyl-benzoic acid

image5

3.3 g of 2,4-bis-benzyloxy-6-ethyl-benzaldehyde are dissolved in 63 ml of DMSO. A solution of 7.9 g of NaClO2 and 7.9 g of NaHCO3 in 32 ml of water is added slowly and under refrigeration, without exceeding the temperature of

5

10

fifteen

twenty

25

30

40 ˚C. Stirring is continued for 2 h, then diluted with more water and extracted twice with EtOAc. The combined organic phases are washed with water, dried with reduced Na2SO4, subjected to silica gel chromatography and crystallized from Me2COH:

Product obtained 2.21 g (64%) of 2,4-bis-benzyloxy-6-ethyl-benzoic acid, F. 126-127˚.

They can be obtained, analogously:

2,4-bis-benzyloxy-6-chloro-benzoic acid, F. 135-136˚ (35%) and 3-chloro-2-ethyl-4-hydroxy-benzoic acid from 3-chloro-2-ethyl-4 -hydroxybenzaldehyde: Result -51% F. 138-139 ˚.

Example 8

2,4-dibenzyloxy-6-ethyl-benzohydrazide.

The substance is obtained according to the method represented in Example 1 from 2,4-bis-benzyloxy-6-ethylbenzoic acid and hydrazinium hydroxide: Result 75% F. 140-141 ˚.

Similarly, 2,4-dibenzyloxy-6-chloro-benzohydrazide is obtained: Product obtained 61%, F. 166-167˚ and 4-benzyloxy-3-chloro-2-ethyl-benzohydrazide. Result 85% F. 182-184 ˚.

Example 9

2,4-bis-benzyloxy-6-chloro-benzaldehyde

image 1

12 g of chloro-3,5-dibenzyloxy-benzole are dissolved in 40 ml of DMF. At 5-10˚ 12 ml of POCl3 is added dropwise. Let stand 90 min at room temperature, then continue the reaction overnight at 80 ° C. The solution is reduced in the rotary evaporator, then it is placed on 200 ml of ice water. It is extracted three times with EtOAc, washed with water, dried and reduced. Chromatography on silica gel yields 8.2 g (63%) of 2,4-bis-benzyloxy-6-chloro-benzaldehyde, crystallized from (Me2C) 2O, F. 85-86˚.

Example 10

Acetoxy- (3-chloro-phenyl) -acetic acid

1 g of racemic 3-chloroamigdálico acid with 2 ml of acetyl chloride. A clear solution is obtained which is reduced after 2 h in the rotary evaporator and crystallized with (Me2C) 2O / petroleum ether. Result: 670 mg (55%) F. 118º.

Example 11

3-Chloro-2-ethyl-4-hydroxy-benzohydrazide.

The compound is obtained by hydrogenation of 300 mg of 3-chloro-2-ethyl-4-benzyloxy-benzohydrazide in 10 ml of MeOH and 145 ml of 32% HCl in Pd / Cu. Result: 165 mg (78%), 233-235˚ (EtOAc / MeCN). They can be obtained, analogously: 5-chloro-2,4-dihydroxy-benzohydrazide, result 84%, F. 260˚.

Example 12

3-Chloro-2-ethyl-4-hydroxy-benzaldehyde.

image 1

5

10

fifteen

twenty

25

30

35

To 4 g of 2-ethyl-4-hydroxybenzaldehyde, dissolved in 80 ml of CHCl3 and 1.5 ml of concentrated HCl, 3.4 g of N-chlorosuccinimide in 40 ml of CHCl3 are added dropwise over a period of time. 45 min. It is stirred for a further 1 h, washed with water, dried and reduced.

Silica gel chromatography results in 1 g (20%) of 3-chloro-2-ethyl-4-hydroxybenzaldehyde (F. 85˚, silica gel polar substance with petroleum ether / ether 1: 1) together with 5-Chloro-2-ethyl-4-hydroxy-benzaldehyde (F. 83˚, medium polarity) and 3,5-dichloro-2-ethyl-4-hydroxy-benzaldehyde (F. 117-118˚, non-polar).

The following examples correspond to pharmaceutical preparations:

Example A: Bottles for injection

A solution of 100 g of an active substance according to the invention and 5 g of dihydrogen sodium phosphate is regulated in 3 I of double-distilled water with 2 n of hydrochloric acid until a pH of 6.5 is reached, it is subjected to sterile filtration, transferred to bottles for injection, lyophilized under sterile conditions and sterile closed. Each vial for injection contains 5 mg of active substance.

Example B: Suppositories

A mixture of 20 g of an active substance according to the invention is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active substance.

Example C: Solution

A solution of 1 g of an active substance according to the invention, 9.38 g of NaH2PO4 · 2 H2O, 28.48 g of Na2HPO4 · 12 H2O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water is prepared . It is regulated at a pH of 6.8, completed to reach 1 I and sterilized through radiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of an active substance according to the invention are mixed with 99.5 g of petrolatum under aseptic conditions.

Example E: Pills

A mixture of 1 kg of active substance, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate are pressed in the usual way to obtain tablets, so that each tablet contains 10 mg of active substance. .

Example F: Dragees

Analogously to example E, the tablets are then pressed which are then routinely coated with a sucrose bath, potato starch, talcum powder, traganto and dye.

Example G: Capsules

2 kg of active substance are usually filled in rigid gelatin capsules, so that each capsule contains 20 mg of the active substance.

Example H: Ampoules

A solution of 1 kg of active substance according to the invention in 60 I of double-distilled water is subjected to sterile filtration, transferred to ampoules, lyophilized under sterile conditions and closed. Each vial contains 10 mg of active substance.

5

10

fifteen

twenty

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30

image6

Claims (30)

1. Compounds of formula I R3, R4, R5, R6, R7, R8, R9, R10, R11 are, respectively, independently of each other H, A, OSO2A, HaI, NO2, OR12, N (R12) 2, CN, O-COA, - [ C (R12) 2] nCOOR12, O- [C (R12) 2] oCOOR12, SO3H, - [C (R12) 2] nAr, -CO-Ar, O- [C (R12) 2] nAr, -C ( R12) 2] nHet, - [C (R12) 2] nC ≡ CH, O- [C (R12) 2] nC ≡ CH, - [C (R12) 2] nCON (R12) 2, - [C (R12 ) 2] nCONR12N (R12) 2, O [C (R12) 2] nCON (R12) 2, O- [C (R12) 2] oCONR12N (R12) 2, NR12COA, NR12CON (R12) 2, NR12SO2A, N ( SO2A) 2, COR12, S (O) mAr, SO2NR12 or S (O) mA, R3 and R4 together are also CH = CH-CH = CH, R3 and R4, R7 and R8 or R8 and R9 are also together alkylene with 3, 4 or 5 C atoms, where one or two CH2 groups may be replaced by oxygen, A is unbranched or branched chain alkyl, with 1-6 C atoms, where 1-7 atoms of H can be replaced by F, or cyclic alkyl with 3 to 7 C atoms, Ar is phenyl, naphthyl or unsubstituted or mono, bi or trisubstituted by Hal, A, OR12, N (R12) 2, NO2, CN, phenyl, CON (R12) 2, NR12COA, NR12CON (R12) 2, NR12SO2A, COR12, SO2N (R12) 2, S (O) mA, - [C (R12) 2] n-COOR12 and / or O [C (R12) 2] o-COOR12, Het may be a saturated or unsaturated aromatic heterocycle with 1 to 4 N, O and / or S atoms, unsubstituted or mono, bi or Trisubstituted by Hal, A, OR12, N (R12) 2, NO2, CN, COOR12, CON (R12) 2, NR12COA, NR12SO2A, COR12, SO2NR12, S (O) mA, = S, = NR12 and / or carbonyl oxygen (= O), R12 is Ho A, Hal is F, Cl, Br or I, m is 0.1 or 2, n is 0, 1.2 or 3, or is 1, 2 or 3, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions. 2. Compounds according to claim 1, wherein R1 is H EIGHT, R2 is H, 5 10 fifteen twenty 25 30 35 as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions. 3. Compounds according to claim 1 or 2, wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 are, respectively, independently of each other, H, A, Hal, OR12 or O [C (R12) 2] nAr, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

Four.

Compounds according to one or more of claims 1-3, wherein R6 is OH,

as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

5.

Compounds according to one or more of claims 1-4, wherein R3 is H, A or Hal,

as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

6.

Compounds according to one or more of claims 1-5, wherein R8 is OH, A, phenoxy or Hal,

as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

7.

Compounds according to one or more of claims 1-6, wherein R4, R5, R7, R9, R10, R11 are H or A,

as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

8.

Compounds according to one or more of claims 1-7, wherein R7, R10, R11 are, respectively independently of each other, H or Hal,

as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

9.

Compounds according to one or more of claims 1-8, wherein Ar, is unsubstituted phenyl or mono or bis-substituted by Hal, and / or A,

as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

10.

Compounds according to one or more of claims 1-9, wherein Ar is phenyl,

as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

eleven.

Compounds according to one or more of claims 1-10, wherein

Het is a saturated, unsaturated or aromatic mononuclear heterocycle with 1 to 2 N and / or O atoms, which can be unsubstituted or mono, bi or trisubstituted by A, Hal, OH and / or OA, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions. 12. Compounds according to one or more of claims 1-11, wherein Het is a mononuclear saturated heterocycle with 1 to 2 atoms of N and / or O, which can be unsubstituted or mono or bis-substituted by A, 5 10 fifteen twenty 25 30 as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions. 13. Compounds according to one or more of claims 1-12, wherein Het is furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl unsubstituted or mono or bi or trisubstituted by A, Hal, OH and / or OA. as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions.

14.

Compounds according to one or more of claims 1-13, wherein R1 is H or CHO R2 is H, R3, R4, R5, R6, R7, R8, R9, R10, R11 are, respectively, independently of each other, H, A, Hal, OR12 or O- [C (R12) 2] nAr; as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all

proportions

fifteen.

Compounds according to one or more of claims 1-14, wherein R1 is H or CHO R2 is H, R3 is H, A or Hal, R4, R5, R7, R9, R10, R11 is H or A, R6 is OH, R8 is OH, A, phenoxy or Hal, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all

proportions

16.

Compounds according to one or more of claims 1-15, wherein R1 is H or CHO R2 is H, R3 is H, A or Hal, R4, R5, R7, R9, R10, R11 is H, A or Hal, R8 and R9 together are also methylenedioxy, R6 is OH, R8 is OH, A, phenoxy or Hal, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all

proportions

17.

Compounds according to one or more of claims 1-16, wherein R1 is H, CHO or acetyl, R2 is H, R3 is H, A or Hal,

R4, R5, R7, R10, R11 are, respectively independently of each other, H, A or Hal, R6 is OH, R8 is OH, A, phenoxy or Hal, R9 is H, Hal or OA, R8 and R9 together are also methylenedioxy, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions 18. Compounds according to claim 1, selected from the group of

Do not

structural formula name

"A1"

N ’- [2- (3,4-Difluoro-phenyl) -2-hydroxy-acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

"A2"

N ’- [2-hydroxy-2- (3-phenoxy-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

(continued) (continued) (continued) (continued)

Do not

structural formula name

"A3"

N ’- (2-hydroxy-2-phenyl-acetyl) -2,4-dihydroxy-6-methyl-benzohydrazide

"A4"

N ’- [2-hydroxy-2- (3-chloro-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

"TO 5"

N ’- [2-hydroxy-2- (3-trifluoromethyl-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

Do not

structural formula name

"A6"

N ’- [2-acetoxy-2- (3-chloro-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

"A7"

N ’- [2-hydroxy-2- (3-fluorine-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

"A8"

N ’- [2-hydroxy-2- (3,5-difluoro-phenyl) -acetyl] 2,4-dihydroxy-6-methyl-benzohydrazide

Do not

structural formula name

"A9"

N ’- [2-hydroxy-2- (2,3,4,5,6-pentafluor-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

"A10"

N ’- (2-benzo [1,3] dioxol-5-yl-2-hydroxy-acetyl) -2,4-dihydroxy-6-methyl-benzohydrazide

"A11"

N ’- [2-hydroxy-2- (3-hydroxy-4-methoxy-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

Do not

structural formula name

"A12"

N ’- [2-hydroxy-2- (3-chloro-phenyl) -acetyl] -2,4-dihydroxy-5-chloro-benzohydrazide

"A13"

N ’- [2-hydroxy-2- (3-chloro-phenyl) -acetyl] -3-chloro-2-ethyl-4-hydroxy-benzohydrazide

"A14"

N ’- [(R) -2- (3-Chloro-phenyl) -2-hydroxy-acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

(continuation)

Do not

structural formula name

"A15"

N ’- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-chloro-4,6-dihydroxy-benzohydrazide

"A16"

N ’- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-methyl-4,6-dihydroxy-benzohydrazide

"A17"

N ’- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2-ethyl-4,6-dihydroxy-benzohydrazide

(continued) (continued)

Do not

structural formula name

"A18"

N ’- (2-hydroxy-2-phenyl-acetyl) -2-methyl-4,6-dihydroxy-benzohydrazide

"A19"

N ’- [2-hydroxy-2- (3-methyl-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

"TO 20"

N ’- [2-hydroxy-2- (3,4-difluoro-phenyl) -acetyl] -2,4-dihydroxy-5-methyl-benzohydrazide

"A21"

N ’- [2-formyloxy-2- (3,4-difluoro-phenyl) -acetyl] -2,4-dihydroxy-6-methyl-benzohydrazide

Do not

structural formula name

"A22"

N ’- [2-hydroxy-2- (3,4-difluoro-phenyl) -acetyl] -2,4-dihydroxy-6-ethyl-benzohydrazide

"A23"

N ’- [2-hydroxy-2- (3,4-difluoro-phenyl) -acetyl] -4-hydroxy-2-ethyl-3-methyl-benzohydrazide

as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions. 19. Process for obtaining compounds of the formula I according to claims 1-18, as well as their salts, solvates and stereoisomers for pharmaceutical use, characterized in that a) a compound of the formula II is reacted image 1 Wherein R1, R7, R8, R9 R10 and R11 have the meaning indicated in claim 1, with a compound of the formula III wherein L is Cl, Br, I or a free or functionally reactive modified OH group, R2, R3, R4 and R5 have the meaning indicated in claim 1 image 1 5 or b) a compound of the formula IV is reacted image 1 where R2, R3, R4, R5 and R6 have the meaning indicated in claim 1 and 10 with a compound of the formula V image 1 where L is Cl, Br, I or a free or functionally reactive modified OH group, R1, R7, R8, R9 R10 and R11 have the meaning indicated in claim 1, 15 oc) a compound of the formula I converts a radical R1, R2, R3, R4, R5, R6, R7, R8, R9 , R10 and / or R11 in another radical R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and / or R11, 10 fifteen twenty 25 30 35 40 dissociating an ether through hydrolysis or hydrogenolysis and / or converting a base or acid of the formula I into one of its salts.

twenty.

Medicines containing at least one compound according to claim 1-18 and / or its salts, solvates and stereoisomers for pharmaceutical use, including mixtures thereof in all proportions, as well as, possibly, excipients and / or adjuvants.

twenty-one.

Use of compounds according to claim 1-18, as well as their salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions, for obtaining a medicament for the treatment and / or prophylaxis of diseases in which The inhibition, regulation and / or modulation of the kinase signal transduction play a role.

22

Use according to claim 21, wherein the kinase is SGK.

2. 3.

Use according to claim 22 of compounds according to claim 1-18, as well as their salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions, for obtaining a medicament for the treatment of diseases in which it is influenced by the inhibition of SGK, through the compounds according to claim 1-18.

24.

Use according to claim 23 of compounds according to claim 1-18, as well as their salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions, for obtaining a medicament for the treatment or prevention of diabetes , adiposity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertonia, diseases of the cardiovascular system and renal diseases, in general, in all types of fibrosis and inflammatory processes, cancer, tumor cells, tumor metastases, coagulopathies, neuronal irritability, glaucoma, cataracts , bacterial infections as well as in an anti-infective therapy, to increase learning capacity and attention, as well as for the treatment and prophylaxis of cellular aging and stress and for the treatment of tinnitus.

25.

Use according to claim 24, wherein, in the case of diabetes, it is diabetes mellius, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.

26.

Use according to claim 24, wherein, in the case of cardiovascular diseases, it is cardiac fibrosis after myocardial infarction, cardiac hypertrophy, heart failure and arteriosclerosis.

27.

Use according to claim 24, wherein, in the case of renal diseases, it is glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and electrolyte elimination failures.

28.

Use according to claim 24, wherein in the case of fibrosis and inflammatory processes it is liver cirrhosis, pulmonary fibrosis, fibrous pancreatitis, rheumatism and osteoarthritis, Crohn's disease, chronic bronchitis, radiogenic fibrosis, sclerodermatitis, cystic fibrosis, formation of scars and Alzheimer's disease.

29.

Medication containing at least one compound according to claim 1-18, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions, and at least one other medicinal substance.

30

Set (kit), consisting of separate packages of

(to)

an effective amount of a compound according to claim 1-18, as well as its salts, solvates and stereoisomers for pharmaceutical use, including mixtures in all proportions,

Y

(b)

an effective amount of another medicinal action substance.